Figure 2.

Multiple mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia. The schematic portrays multiple mechanisms of TKI resistance, including BCR-ABL1 kinase-dependent mechanisms (top) and BCR-ABL1 kinase-independent mechanisms (bottom). Certain tyrosine kinase mutations impart increased or decreased fitness on the BCR-ABL1 kinase. Other mutations such as T315I impart high-level resistance to first- and second-generation TKIs. Cells that carry resistance mutations may impart resistance on neighboring bystander cells by secretion of paracrine factors (such as the cytokine IL-3), so that even cells with native BCR-ABL1 become TKI resistant. Last, CML cells may acquire resistance through intrinsic activation of alternative signaling pathways or through interaction with the bone marrow microenvironment. Red and green dots denote paracrine factors produced by leukemic cells or the bone marrow microenvironment.